2-cyano-pyrimidines and-triazines as cysteine protease inhibitors
a technology of cysteine protease and triazines, which is applied in the direction of biocide, heterocyclic compound active ingredients, drug compositions, etc., can solve the problems of cancer and disease, common cause of death in humans and other warm-blooded animals, and achieve the effect of reducing the number of side effects
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example 1
4-(4′-Aminomethyl-biphenyl-3-yloxy)-pyrimidine-2-carbonitrile, Salt with Formic Acid
[0174]A solution of [3′-(2-cyano-pyrimidin-4-yloxy)-biphenyl-4-ylmethyl]-carbamic acid tert-butyl ester (10 mg) in formic acid (0.154 ml) is stirred at rt for 1 h. This solution is evaporated under reduced pressure. The remaining oil is treated with diethyl ether to obtain crystals of 4-(4′-aminomethyl-biphenyl-3-yloxy)-pyrimidine-2-carbonitrile as salt with formic acid.
[0175]MS (ESI+): 303 [M+Na]; Rf: (DCM / MeOH=9 / 1, 1% NH3aq.): 0.45; 1H-NMR (400 MHz, d6-DMSO): delta=8.88 (d, 1H); 8.36 (s, 1H); 7.75-7.50 (m, 8H); 7.32 (d, 1H); 3.85 (s, 2H).
[0176]The starting materials are prepared as follows:
Stage 1.1: (3′-Hydroxy-biphenyl-4-ylmethyl)-carbamic acid tert-butyl ester
[0177]A mixture of (4-bromo-benzyl)-carbamic acid tert-butyl ester (600 mg), 3-hydroxybenzeneboronic acid (373 mg), sodium carbonate (333 mg), palladium (II) acetate (10 mg) and tricyclohexylphosphine (13 mg) in water (3.5 ml) and dioxane (...
example 2
4-(4′-Aminomethyl-biphenyl-3-ylamino)-[1,3,5]triazine-2-carbonitrile, Salt with Formic Acid
[0183]A solution of [3′-(4-cyano-[1,3,5]triazin-2-ylamino) -biphenyl-4-ylmethyl]-carbamic acid tert-butyl ester (43 mg) in formic acid (1 ml) is stirred at 5° C. for 4.5 h. This solution is evaporated under reduced pressure. The remaining oil is treated with diethyl ether to obtain crystals of 4-(4′-aminomethyl-biphenyl-3-ylamino)-[1,3,5]triazine-2-carbonitrile, salt with formic acid.
[0184]MS (ESI+): 303 [M+H]; Rf: (DCM / MeOH=9 / 1, 1% NH3aq.): 0.33; 1H-NMR (300 MHz, d6-DMSO): delta=8.88 (s, 1H); 8.28 (s, 1H); 7.92 (s, br, 1H); 7.65-7.4 (m, 7H); 3.98 (s, 2H).
[0185]The starting materials are prepared as follows:
Stage 2.1: [3′-(4-Chloro-[1,3,5]triazin-2-ylamino)-biphenyl -4-ylmethyl]-carbamic acid tert-butyl ester
[0186]A mixture of (3′-amino-biphenyl-4-ylmethyl)-carbamic acid tert-butyl ester (48 mg), 2,4-dichlorotriazine (20 mg) and sodium carbonate in acetonitrile (1.5 ml) is stirred at 0° C. for...
example 3
N-[3′-(2-Cyano-pyrimidin-4-yloxy)biphenyl-4-yl]-guanidine, Salt with Trifluoroacetic Acid
[0190]A mixture of N-[3′-(2-chloro-pyrimidin-4-yloxy)biphenyl-4-yl]-guanidine (66 mg), potassium cyanide (35 mg) and 1,4-diazabicyclo[2,2,2]octane (6 mg) in water (0.2 ml) and DMSO (1 ml) is stirred at rt for 2.5 h. This mixture is acidified with trifluoroacetic acid to pH 4-5 and purified by preparative HPLC (gradient of water, 0.1% TFA / acetonitrile, 0.1% TFA from 80 / 20 to 0 / 100 on Nucleosil 100-10 C18 column). The fractions containing product are lyophilized giving the trifluoroacetate salt of N-[3′-(2-cyano-pyrimidin-4-yloxy)biphenyl-4-yl]-guanidine.
[0191]MS (ESI+): 331 [M+H]; Rf: (EtOAc / AcOH=10 / 1): 0.22.
Stage 3.1: N-(3′-hydroxy-biphenyl-4-yl)guanidine
[0192]A mixture of 4-chlorophenylguanidine carbonate (644 mg), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (373 mg), sodium carbonate (495 mg), palladium (II) acetate (14 mg) and tricyclohexylphosphine (19 mg) in water (1.2 ml) and dio...
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